Drug delivery system with means for obtaining desirable in vivo release rate pattern

ABSTRACT

A delivery device is disclosed for delivering a beneficial drug to a biological environment of use. The device comprises a hydrogel reservoir containing tiny pills. The tiny pills comprise a wall surrounding a drug core.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. pat. appln. Ser. No.07/014,944 filed Feb. 13, 1987, now U.S. Pat. No. 4,764,380 issued Aug.16, 1988 which appln. Ser. No. 07/014,944 is a continuation of U.S. pat.appln. Ser. No. 06/571,299 filed Jan. 16, 1984 now U.S. Pat. No.4,649,043 issued Mar. 10, 1987 which appln. Ser. No. 06/571,299 is acontinuation of U.S. pat. appln. Ser. No. 06/360,477 filed Mar. 22, 1982now U.S. Pat. No. 4,434,153 issued Feb. 28, 1984, which appln. Ser. No.06/571,299 is copending with U.S. pat. appln. Ser. No. 06/571,618 filedJan. 1, 1984 now U.S. Pat. No. 4,659,588 issued Apr. 21, 1987 and iscopending with U.S. pat. appln. Ser. No. 06/571,009 filed Jan. 16, 1984now U.S. Pat. No. 4,642,233 issued Feb. 10, 1987. These applications areincorporated herein by reference and benefit is claimed of their fillingdates. These applications are assigned to ALZA Corporation of Palo Alto,CA.

FIELD OF THE INVENTION

This invention pertains to a drug delivery system manufactured in theform of a drug delivery device. More particularly, the inventionpertains to a drug delivery device comprising an in vivo reservoir thatis a means for remaining in the stomach over a prolonged period of time.The reservoir comprises at least one expandable material comprising aplurality of tiny pills.

BACKGROUND OF THE INVENTION

A long-felt need exists for a drug delivery system for remaining in thestomach over a prolonged period of time. The need exists for a drugdelivery system that remains in the stomach and acts as an in vivoreservoir that releases drug at a controlled rate and continuously for(a) absorption in the stomach or for (b) passage into the intestine forabsorption therein. Drug delivery systems are used clinically foradministering a drug for its beneficial effect. Often the drug isadministered from (1) a delivery system that releases a drug over timeas the system moves through the gastrointestinal tract or from (2) adelivery system that remains in the stomach and releases drug while inthe stomach. The delivery systems are used because they eliminate theneed for administering a number of single doses at periodic intervals.The convenience of using a drug delivery system, which releases drugover a prolonged period of time as opposed to the administration of anumber of doses, has long been recognized in the practice of medicine.The preferred sought-after therapeutic advantage to the patient and theclinician is controlled and optimum blood levels of drug during theperiod of time drug is released from the delivery system. This advantagearises from the delivery system continuously supplying drug for itspassage and absorption into the blood for replacing drug used,eliminated, or metabolically inactivated by the patient.

The above presentation teaches that delivery systems have been providedfor supplying continuously and for obtaining better therapy in themanagement of health and disease. For example, one system used for thecontinuous release of drug over a long period of time is disclosed bypatentee Blythe in U.S. Pat. No. 2,738,303. The delivery systemdisclosed in this patent consists essentially of a capsule containinguncoated pellets of drug and coated pellets of drug having varyingthickness. On their release from the capsule, the uncoated pelletsprovide an initial amount of drug and the coated pellets provide drugover a period of time. Another delivery system is disclosed by patenteesSheth et al in U.S. Pat. Nos. 4,140,775 and 4,167,558. The systemsdisclosed in these latter patents consists essentially of a tabletformed of a compressed polymer containing dispersed drug. The system ishydrodynamically balanced for remaining in the stomach for releasingdrug therein over time.

While the above delivery systems are designed for providing a continuoussupply of drug, there are inherent short-comings associated with thesedelivery systems. For example, pellets often pass through thegastrointestinal tract quickly, and this tends to limit the supplying ofdrug needed for maintaining a desired blood level of drug. Also, pelletsare not designed for remaining in the stomach over an extended period oftime as they tend to empty from the stomach in a first order manner likeliquids. The tablet, on its exposure to stomach fluid, releases drug byuncontrolled leaching action and at a declining rate, which actionsrestrict the use of the tablet as a controlled delivery system duringthe time of its residency in the stomach.

In view of the above presentation, it will be appreciated by thoseversed in the drug dispensing art that if a delivery system is providedthat remains in the stomach and acts as an in vivo drug reservoir whileconcurrently releasing drug in the stomach for (a) absorption in thestomach, or for (b) passage into the intestine for absorption therein,essentially without disrupting the normal emptying of ingested foods andliquids, such a delivery system would have a positive value andrepresent a substantial contribution to the dispensing art. Likewise, itwill be appreciated by those skilled in the eart, that if a deliverysystem is made available that remains in the stomach for releasing drugat a controlled rate over time for achieving therapeutic blood levels,such a delivery system would be clinically useful in the practice ofmedicine.

OBJECTS OF THE INVENTION

Accordingly, in view of the above presentation, it is an immediateobject of this invention to provide a novel and useful drug deliverysystem that satisfies the long-felt need and overcomes the shortcomingsknown to the prior art.

Another object of the invention is to provide a drug delivery devicethat is simple in construction and which device exhibits all of thepractical benefits of controlled and continuous administration of drugto animals and humans over a prolonged period of time.

Another object of the invention is to provide a drug delivery systemmanufactured in the form of a drug delivery device for prolongedresidency in the stomach for executing a therapeutic program therein.

Still another object of the invention is to provide a drug deliverydevice comprising a reservoir formed of an expandable materialcontaining tiny pills, which device is useful for maintaining thestomach in the fed mode and/or for concomitantly keeping the housekeeperaway from extending the stomach residence of the drug delivery device.

Yet another object of the invention is to provide a drug delivery devicecomprising a swellable reservoir containing tiny pills for remaining inthe stomach an extended period of time for making a drug availabletherein, or for its subsequent passage into the intestine.

yet still another object of the invention is to provide a drug deliverydevice that by its in vivo size will be retained in the stomach duringthe fed mode and, prior to its passage into the small intestine,bioerode in the stomach over time.

Yet still another object of the invention is to provide a drug deliverydevice dimensioned to be retained in the stomach for delivering drug inthe stomach and hence into the intestine.

Another object of the present invention is to provide a drug deliverydevice comprising a reservoir that houses a multiplicity of tiny pills,which tiny pills comprise a drug that is from poorly soluble to verysoluble in an aqueous media, which drug can now be delivered at a ratecontrolled by the dosage form and at a continuous rate for a particulartime period, the use of which delivery device requires intervention onlyfor initiation of the drug delivery regimen.

Another object of the invention is to provide a delivery devicecomprising a reservoir and a plurality of tiny pills, which two membersfunction as a cooperating unit for administering from low to high dosesof a drug at a controlled rate to the gastrointestinal tract over aprolonged period of time.

Other objects, features, aspects and advantages of the invention will bemore apparent to those versed in the dispensing art from the followingdetailed specification taken in conjunction with the drawing figures andthe accompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not drawn to scale but are set forth toillustrate various embodiments that can be provided by the invention thedrawing figures are as follows:

FIG. 1 is a view of an oral drug delivery device provided by theinvention;

FIG. 2 is an opened view in cross-section through 2--2 of FIG. 1;

FIG. 3 is an opened view of the delivery system depicting the deliverysystem in an expanded, swollen state; and,

FIG. 4 depicts a multiplicity of tiny pills, some in openedsection, ontheir release from the supporting delivery system.

In the drawing figures and in the specification, like parts in relatedfigures are identified by like numbers. The terms appearing earlier inthe specification and in the description of the drawing figures, as wellas embodiments thereof, are further described elsewhere in thedisclosure.

DETAILED DESCRIPTION OF THE DRAWINGS

Turning now to the drawings in detail, which are an example of variousdrug delivery device provided by the invention, and which example is notto be construed as limiting, one example of a drug delivery device isseen in FIGS. 1 through 3, considered together, and indicated by numeral10.

In FIGS. 1 through 3, device 10 is seen comprising a body 11 tht isadapted, shaped and sized for oral admittance into the gastrointestinaltract for extended residency in the stomach. In FIGS. 2 and 3, seen inopened section, body 11 comprises a reservoir 12 formed of a non-toxicmaterial that expands and swells in the presence of fluid in theenvironment of use, such as water or gastric fluid. The material formingreservoir 12 in a presently preferred embodiment comprises a hydrophilicpolymer, such as a hydrogel. In FIG. 2, reservoir 12 is made of ahydrophilic material as it is illustrated in a non-hydrated state. InFIG. 3 reservoir 12 is illustrated in an enlarged state as the reservoirabsorbs and imbibes fluid from the environment of use and swells orexpands to some equilibrium state. This increase in size acts as a meansfor retaining device 10 in the stomach over an extended period of time.Reservoir 12 leaves the environment of use by hydrolyzing,disintegrating or bioeroding during and at the end of the drug deliveryperiod. A description of materials useful for forming reservoir 12appears later in the specification.

Drug delivery device 10 of FIGS. 1 through 3, seen in opened view inFIGS. 2 and 3, houses a multiplicity of tiny pills 13 for the controlleddelivery of drug over time. In FIG. 4, tiny pills 13 are seen in detailafter third release from reservoir 12, and they 13 comprise a core ofdrug 14 surrounded by a wall 15 formed of a release rate controllingmaterial. Tiny pills 13, in one embodiment, can have wall 15 made from amaterial that releases drug 14 in the stomach or, in another embodiment,tiny pills 13 can have a wall 15 made from an enteric material whichprevents release of drug 14 in the stomach, but will release drug 14 inthe intestine. Additionally, the materials forming wall 15 can beselected from materials that release drug 14 by differentphysical-chemical mechanisms. These mechanisms include erosion,dissolution, diffusion, osmosis, osmotic bursting, metabolism, and thelike. Wall 15 can have various thicknesses as an additional aid forproviding timed release of drug. A description of wall forming materialsappears later in the specification.

In operation, device 10 resides in the stomach for an extended period oftime by concurrently (1) enlarging in the stomach, and by (2) keepingthe stomach in the fed mode. Device 10 delivers drug 14 (a) in thestomach by non-enteric coated tiny pills 13 releasing drug over time,and (b) in the intestine by device 10 releasing enteric coated tiy pills13 for their passage into the intestine wherein tiny pills 13 deliverdrug 14 over a prolonged period of time.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the practice of the invention, delivery device 10 canbe made with a reservoir 12 of a material that does not adversely affectdrug 14, an animal or other host. The presently preferred materialsuseful for forming reservoir 12 comprise hydrogels that exhibit theability to swell in water and retain a significant fraction of waterwithin its structure. In one embodiment, the hydrogels can benoncross-linked, or in another embodiment they may be cross-linked withan acid mobile covalent or ionic bonds sensitive to slow acidichydrolysis. The term mobile is used in its standard meaning to denotethe bond breaks in an acidic environment. The hydrogels can be selectedfrom the group consisting of plant or animal origin, hydrogels preparedby modifying naturally occurring structures, and synthetic polymerichydrogels. The polymeric hydrogels swell or expand to a very highdegree, usually exhibiting a 2 to 50 fold volume increase. Hydrophilicpolymeric materials useful for the purpose include poly(hydroxyalkylmethacrylate); poly(electrolyte complexes); poly(vinyl acetate)cross-linked with hydrolyzable bonds; waterswellable N-vinyl lactams;polysaccharides; natural gum; agar; agrose; sodium alginate;carrageenan; fucoidan; furcellaran; laminaran, hypnea; eucheuma; gumarabic; gum ghatti; gum karaya; gum tragacanth; locust beam gun;chitosan; arbinoglactan; pectin; amylopectin; gelatin; hydrophiliccolloids such as carboxymethyl cellulose gum or alginate gumcrossed-linked with a polyol such as propylene glycol; and the like,cellulose ethers comprising hydroxypropylmethylcellulose exhibiting aviscosity of from 3 to 260,000 centipoises, a degree of polymerizationof from 40 to 2100, and a molecular weight having a number average offrom 9,200 to 350,000; and hydroxypropylcellulose ether having ahydroxypropyl content of 7 to 16%.

Representative of hydroxypropylmethylcellulose ethers useful for thepurpose of this invention are as follows: (a)hydroxypropylmethylcellulose having a viscosity of 3, a degree ofpolymerization (DP) of 48, and a number average molecular weight(MW_(n)) of 9,200; (b) hydroxypropylmethylcellulose having a viscosityof 3, a degree of polymerization of 48, and a number average molecularweight of 9,600; (c) a hydroxypropylmethylcellulose having a viscosityof 5, a degree of polymerization of 56, and a number average molecularweight of 11,300; (d) a hyroxypropylmethylcellulose having a viscosityof 6, a degree of polymerization of 59 and a number average molecularweight of 11,900; (e) hydroxypropylmethylcellulose having a viscosity of14, a degree of polymerization of 77 and a number average molecularweight of 14,300; (f) a hydroxypropylmethylcellulose possessing aviscosity of 15, a degree of polymerization of 79, and a number averagemolecular weight of 15,900; (g) a hydroxypropylmethylcellulose having aviscosity of 35, a degree of polymerization of 102, and a number averagemolecular weight of 19,600; (h) a hydroxypropylmethylcellulose having aviscosity of 50, a degree of polymerization of 116, and a number averagemolecular weight of 22,600; (i) a hydroxypropylmethylcellulose having aviscosity of 50, a degree of polymerization of 116, and a number averagemolecular weight of 23,300; (j) a hydroxypropylmethylcellulose having aviscosity of 100, a degree of polymerization of 145, and a numberaverage molecular weight of 27,800; (k) a hydroxypropylmethylcellulosehaving a viscosity of 106, a degree of polymerization of 156 and anumber average molecular weight of 30,000; (l) ahyroxypropylmethylcellulose having a viscosity of 400, a degree ofpolymerization of 220, and a number average molecular weight of 42,900;(m) a hyroxypropylmethylcellulose comprising a viscosity of 1,500, adegree of polymerization of 335 and a number average molecular weight of65,300; (n) a hydroxypropylmethylcellulose ether comprising a viscosityof 4,000, a degree of polymerization of 460 and a number averagemolecular weight of 88,300; (o) a hydroxypropylmethylcellulosecomprising a viscosity of 4,000, a degree of polymerization of 460, anda number average molecular weight of 92,000; (p) ahydroxypropylmethylcellulose ether comprising a viscosity of 15,000, adegree of polymerization of 690, and a number average molecular weightof 132,500; (q) a hydroxypropylmethylcellulose having a viscosity of18,000, a degree of polymerization of 720, and a number averagemolecular weight of 133,900; (r) a hydroxypropyl methylcellulose ethercomprising a viscosity of 30,000, a degree of polymerization of 860 anda number average molecular weight of 165,100; (s) ahydroxypropylmethylcellulose comprising a viscosity of 100,000, a degreeof polymerization of 1,260 and a number average molecular weight of241,900; (t) a hydroxypropylmethylcellulose comprising a viscosity of220,000, a degree of polymerization of 1,600, and a number averagemolecular weight of 307,200; and (u) a hydroxypropyl methylcellulosehaving a viscosity of 258,000, a degree of polymerization of 2,010 and anumber average molecular weight of 350,000. Viscosity is related tonumber average molecular weight and it is determined from measurementson aqueous solutions of the cellulosic ether polymer.

The expression "hydroxypropylcellulose", as used for the purpose of thisinvention, comprises a hydroxypropylcellulose having a hydroxypropylcontent of 7 to 16% and, more specifically, a hydroxypropylcellulosehaving a hydroxypropyl content of 7 to 10%, a hydroxypropyl content of10 to 13%, and a hydroxypropyl content of 13 to 16%. Cellulose ethersare knwn to the art in U.S. Pat. Nos. 3,870,790; 4,140,755; 4,167,588;4,226,849; 4,259,314; 4,357,469, 4369,172; 4,389,393; and 4,540,566.

Other hydrogels include hydrophilic hydrogels comprising Carbopol®polyacrylamides, Good-rite® polyacrylic acid, polyethylene oxide, starchgraft copolymers, Aqua-Keeps® acrylate polymer ester cross-linkedpolyglucan, and the like. The hydrogels are known to the prior art inU.S. Pat. Nos. 3,640,741, 3,865,108; 3,992,562, 4,002,173; 4,014,335;and 4,207,893; and in Handbook of Common Polymers by Scott and Roff,published by the Chemical Rubber Company; Cleveland, OH.

In one embodiment, wall 15 of tiny pills 13 surrounding drug 14comprises a wall-forming composition consisting essentially of a fattyester mixed with a wax. The fatty ester comprise a member such as atriglyceryl ester selected from the group consisting of glyceryldistearate, glyceryl tristearate, glyceryl monostearate, glyceryldipalmitate, glyceryl tripalmitate, glyceryl monolaurate, glyceryldidocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate,glyceryl monocaprate, glyceryl dicaprate, glyceryl tricaprate, glycerylmonomyristate, glyceryl dimyristate, glyceryl trimyristate, glycerylmonodecenoate, glyceryl didecenoate and glyceryl tridecenoate.

The wax included in the wall forming composition comprise a memberselected from the group consisting essentially of beeswax, cetylpalmitate, spermacetic wax, carnauba wax, cetyl myristate, cetylpalmitate, ceryl cerotate, stearyl palmitate, staryl myristate andlauryl laurate.

The composition comprising the ester and the wax can be coated around thdrug by using an organic solvent such as a member selected from thegroup consisting of carbon tetrachloride, chloroform, trichloroethylene,ether, benzene, ethyl acetate, methyl ethyl ketone, isopropyl alcohol,and the like. The fatty esters, waxes, solvents and procedures formaking tiny pills that slowly disintegrate and continuously provide drugover a period of 10 to 12 hours are disclosed in U.S. Pat. No.2,793,979.

Wall 15 of tiny pills 13, in another embodiment, comprises an osmoticwall forming material that releases drug 14 at a controlled rate by theprocess of osmotic bursting over time. Drug 14 in this embodiment ispresent in the form of an osmotic solute, such as a therapeuticallyacceptable salt, and it exhibits an osmotic pressure gradient acrosswall 15 against an external fluid. The membrane material used to formwall 15 are those permeable to the passage of an external fluid andsubstantially impermeable to the passage of drug. Typical materialsinclude a member selected from the group consisting of celluloseacylate, cellulose diacylate, cellulose triacylate, cellulose acetate,cellulose diacetate, cellulose triacetate, cellulose acetate having adegree of substitution, D.S., up to 1 and an acetyl content of 21%,cellulose diacetate having a D.S. of 1 to 2 and an acetyl content of 21to 35%, cellulose triacetate having a D.S. of 2 to 3 and an acetylecontent of 35 to 44.8%, cellulose acetyl propionate, cellulose acetatebutyrate, and the like. The osmotic wall can be coated around the drugin varying thickness by pan coating, spraypan coating, Wurster® fluidair-suspension coating and the like. The wall is formed using organicsolvents, including those mentioned above, and solvent systems such asmethylene chloride-methanol, methylene chloride-acetone,methanol-acetone, ethylene dichlorideacetone, and the like. Osmotic wallforming material, procedures for forming the wall, and osmotic burstingprocedures are disclosed in U.S. Pat. Nos. 2,799,241; 3,952,741;4,014,334; and 4,016,880.

Wall 15 in another embodiment can comprise a drug release ratecontrolling material. That is, drug 14 dissolves in the wall and passesthrough the wall at a controlled rate over time. Exemplary materialsuseful for forming a diffusional drug release rate controlling wallinclude ethylene-vinyl acetate, ethyl cellulose, polyethylene,cross-linked polyvinyl pyrrolidone, vinylidene chlorideacrylonitrilecopolymer, polypropylene, silicone, and the like. The wall can beapplied by the techniques described above, and materials suitable forforming wall 15 are described in U.S. Pat. Nos. 3,938,515; 3,948,262;and 4,014,335.

In still another embodiment wall 15 can comprise a bioerodible materialthat bioerodes at a controlled rate and releases drug 14 to thebiological environment of use. Bioerodible materials useful for formingwall 15 include polyvalent acid or alkali mobile cross-linkedpolyelectrolytes, polycarboxylic acid, polyesters, polyamides,polyimides, polylactic acid, polyglyolic acid, polyorthoesters, andpolyorthocarbonates. The polymers and procedures for forming wall 15 aredisclosed in U.S. Pat. Nos. 3,811,444; 3,867,519; 3,888,975; 3,971,367;3,993,057; and 4,138,344.

In the specification and the accompanying claims the term "drug"includes pharmacologically active substances that produce a local orsystemic effect in animals, which term includes warm-blooded mammalssuch as humans. The active drug that can be delivered includes drugsthat act on the central nervous system, depressants, hypnotics,sedatives, psychic energizers, tranquilizers, anticonvulsants, musclerelaxants, antiparkinson agents, analgesics, anti-inflammatory, hormonalagents, contraceptives, sympathomimetics, diuretics, antiparasites,neoplastics, hypoglycemics, ophthalmics, electrolytes, cardiovasculardrugs, and the like.

Exemplary drugs that are soluble in water and can be delivered by thedevices of this invention include prochlorperazine edisylate, ferroussulfate, aminocaproic acid, potassium chloride,mecamylaminehydrochloride, procainamide hydrochloride, amphetamine sulfate,benzhetamine hydrochloride, isoproternol sulfate, methamphetaminehydrochloride, phenmetrazine hydrochloride, bethanechol chloride,methacholine chloride, atropine sulfate, methascopolamine bromide,isoprompamide iodide, tridihexethyl chloride, oxprenolol hydrochloride,metoprolol hydrochloride, cimetidine hydrochloride, and the like.

Exemplary drugs that have limited solubility in water and can bedelivered by devices of this invention include meclizine hydrochloride,phenoxybenzamine, thiethylperazine maleate, anisindone, erythrityltitranitrate, dizoxin, reserpine, acetazolamide, methazolamide,bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone acetate,aluminum aspirin, methotrexate, acetyl sulfisoxazole, erythromycin,progestins, estroginie, progestational, corticosteroids, and the like.

Examples of other drugs that can be delivered by the devices includeaspirin, indomethacin, naproxen, fenoprofen, sulidac, diclofenac,indoprofen, propranolol, metroprolol, oxprenolol, timolol, chlonidine,theophylline, ferrous lactate, phenoxybenzamine, baclofen, furosemide,and the like. The beneficial drugs are known in the art inPharmaceutical Sciences, by Remington, 14th Ed., 1979, published by MackPublishing Co.; The Drug, The Nurse, The Patient, Including Current DrugHandbook, by Falconer et al., 1974-1976, published by Saunder Company;and Medicinal Chemistry, 3rd Ed., Vol 1 and 2, by Burger, published byWiley-Interscience Co.

The drug can be present in the tiny pills in various forms, such asunchanged molecules, molecular complexes, therapeutically acceptablesalts such as hydrochlorides, hydrobromide, sulfates, oleates, and thelike. For acid drugs, salts of metals, amines, or organic cations,quaternary ammonium salts can be used. Derivatives of drugs such asesters, ethers and amides can be used. Also, a drug that is waterinsoluble can be used in a form that is the water soluble derivativethereof to serve as a solute and, on its release from the device, isconverted by enzymes, hydrolyzed by body pH, or other metabolicprocesses to the original biologically active form. The amount of drugpresent in a tiny times pill generally is about 10 ng to 50 mg, and thenumber of tiny pills in an oral device is about 10 to 1000, preferably100 to 1000. The tiny pills comprising the wall and inner core of drughave a diameter of at least 0.1 mm to 7.5 mm and, in a presentlypreferred embodiment, a diameter of 0.5 mm to 5 mm. For oral use thedelivery device comprising the reservoir and the tiny pills,homogeneously or heterogeneously housed therein, can have a conventionalshape such as round, oval and the like. The device can have a totaldiameter of 12 mm to 15 mm, and the like.

The following examples will further serve to illustrate the invention.

EXAMPLE 1

An orally administrable tablet containing tiny pills of asympathomimetic drug is prepared as follows: first, powdered drug ismixed with sucrose and the blend passed through a 15 to 30 mesh screento yield a multiplicity of cores of drug. Then, a wall-formingcomposition comprising 85% glycerol monostearate and 15% beeswax in warmcarbon tetrachloride is sprayed over cores in a revolving coating panuntil a wall is formed that individually surrounds the cores. Next,after the coating is stripped from the tiny pills, a series of oraltablets are prepared by blending about 50 tiny pills with about 200 mgof ground reservoir forming carboxy-vinyl polymer, commerciallyavailable as Carbopol® polymer, and then pressing the latter blend in atableting machine under a pressure of 4 kg to yield the delivery device.

EXAMPLE 2

Additional drug delivery devices are provided by coating a drug core,for example, procainamide hydrochloride, in a fluid air suspensionmachine with a composition of ethylcellulose in ethanol to surround thedrug with a wall of procainamide hydrochloride, yielding tiny pillsthereof. After the solvent is vacuum stripped from the tiny pills theyare blended with ground, lightly crosslinked polacrylamide and pressedinto an oral tablet.

EXAMPLE 3

The above manufacture can be repeated by replacing the ethylcelluloseand ethanol with cellulose acetate having and acetyl content of 32% andmethylene chloride-methanol solvent; or by applying a bioerodible wallof poly(2,2-dioxotrans-1,4-cyclohexane dimethylene tetrahydrofuranaround the tiny pills. The latter polymer is applied by heating thepolymer to 80°-90° C. and then dispersing the tiny pills in the polymer.

EXAMPLE 4

In another example, a delivery device is made by first preparingsustained release tiny pills by blending 400 ml of ethyl cellulosewater,70:30% solution, 7.5% w:v, with 375 g of theophylline, 150 g of mannitoland 475 g of magnesium stearate and the blend kneaded and passed throughan extrusion granulation machine. After drying at 115°-120° F., thecores are passed through a 20 mesh screen and coated with a wall ofethyl cellulose in an air suspension machine to yield tiny timed pills.Next, a multiplicity of tiny pills are blended with a hydrogel reservoirforming polymer consisting essentially of a coherent meshwork thatimbibes and immobilizes water, powdered alginate gugm crossed-linkedwith propylene glycol, and the mixture is compressed in a tablet machineusing 11/32 inch deep concave punch to yield the drug delivery devicefor orally administering as a bronchodilator in the management of statusasthmaticus, and as a pulmonary vasodilator and smooth muscle relaxant.Other forms of theophylline can be used in the subject delivery devicesuch as theophylline sodium acetate, theophylline sodium glycinate,{7-(2,3-dihydroxypropyl)] theophylline, theophylline meglumine andtheophylline monoethanolamine.

EXAMPLE 5

An oral administrable delivery tablet is provided by coating a drug corecomprising procainamide hydrochloride in a fluid air suspension machinewith a composition of ethyl cellulose in ethanol to coat a wall of ethylcellulose around the inner core of drug. After the solvent is vacuumremoved from the tiny pills, the pills are housed in a matrix ofhydroxypropylmethylcellulose, The hydroxypropylmethylcellulose exhibiteda degree of polymerization of 460 and a number average molecular weightof 89,7000. The hydroxypropylmethylcellulose is presieved through a 40mesh screen, and magnesium stearate is added thereto. Then, the tinypills are blended with the hydroxypropylmethylcellulose and theresulting blend is compressed with a tablet press at 2 tons pressureusing a standard concave punch.

EXAMPLE 6

An oral administrable delivery tablet is provided by coating a drug coreof isosorbide dinitrate with a cellulose acetate wall having an acetylcontent of 32%. A methylene chloride-methanol solvent is used as thecarrier for the cellulose acetate in an air suspension coater. After thesolvent is evaporated, the pills are housed in a matrix comprisinghydroxypropylmethylcellulose. The hydroxypropylmethylcellulose exhibiteda degree of polymerization of 690 and a number average molecular weightof 133,900. The hydroxypropylmethylcellulose is blended with the tinypills and magnesium stearate. The composition is pressed under apressure head of 1 ton to yield the delivery system.

EXAMPLE 7

Other drug delivery systems are made by spraying nonpareil cores with anedible adhesive and then dusting with drug. The drug-coated core iscoated with an appropriate number of edible enteric coatings to giveenteric coated tiny pills. The number of enteric coats is variable,usually at least 1 to 10 separate coats are used for the presentpurpose. Finally, the tiny pills are housed in the hydrogel reservoir.Manufacturing procedures for the tiny pills are taught in U.S. Pat. No.3,365,365. Also, the tiny pills can be made from a core of carbohydrate,such as sucrose, dusted with a mixture of talc, starch and galactose,moistened with distilled or deionized water, and then dusted with thedesired medicinal, such as the antibiotic erthromycin. The pills aredried and then coated with an outer layer of a non-toxic, acidic,enteric wall formerly selected from the group consisting of keratin,calcium alginate, shellac, partially hydrolyzed styrene-maleic acidcopolymer, polyvinylacitate phthalate, polyvinyl hydrogenphthalate, andthe like. Finally, the pills are dispersed in a hydrogel reservoirmatrix sized, shaped and adapted for oral admittance into thegastrointestinal tract. Procedures for manufacturing the tiny pills aredisclosed in U.S. Pat. No. 3,081,233.

It will be appreciated by those versed in the art, the present inventionmakes available novel and useful delivery devices for dispensing abeneficial drug over a prolonged period of time. Also, it will beunderstood by those knowledged in the dispensing art, that manyembodiments of this invention can be made without departing from thespirit and scope of the invention, and the invention is not to beconstrued as limited, as it embraces all equivalents therein.

We claim:
 1. A drug delivery device for the controlled delivery of abeneficial drug to an environment of use over a prolonged period oftime, the delivery device comprising:(a) a reservoir comprising apharmaceutically acceptable hydroxypropylmethylcellulose; and, (b) aplurality of tiny pills housed in the reservoir, the tiny pillscomprising:(1) a core of a beneficial drug; and, (2) a wall comprisingin at least a part a drug release rate controlling cellulosic polymercomprising an acetyl content of 21 to 44.8% that surrounds the core ofthe beneficial drug and releases the drug when the device is in use inthe environment of use.
 2. The drug delivery device for the controlleddelivery of the beneficial drug according to claim 1, wherein theenvironment of use is the gastrointestinal tract, the drug is abeneficial gastrointestinal administrable drug, and thehydroxypropylmethylcellulose comprises a viscosity of from 3 to 258,000,a degree of polymerization of from 48 to 2,000 and a number averagemolecular weight of from 9,200 to 350,000.
 3. A drug delivery device forthe controlled delivery of a beneficial drug to an environment of useover a prolonged period of time, the delivery device comprising:(a) areservoir comprising a hydroxypropylmethylcellulose; and, (b) amultiplicity of tiny pills housed in the reservoir, the tiny pillscomprising:(1) a dosage unit amount of a beneficial drug; (2) a wallcomprising in at least a part etyl cellulose that surrounds thebeneficial drug and releases the beneficial drug when the device is inoperation in the environment of use.
 4. The drug delivery device for thecontrolled delivery of a beneficial drug according to claim 3, whereinthe environment of use is the gastrointestinal tract the drug is abeneficial gastrointestinal administrable drug, the delivery device isadmittted orally into the gastrointestinal tract, and thehydroxypropylmethylcellulose comprises a viscosity of from 3 to 258,000centipoises, a degree of polymerization of from 48 to 2,000, a numberaverage molecular weight of from 9,200 to 350,000, and exhibits a 2 to50 fold volume increase in the fluid environment of the gastrointestinaltract.
 5. A drug delivery device for the controlled delivery of abeneficial drug to an environment of use over a prolonged period oftime, the delivery device comprising:(a) a matrix shaped and sized fororal admittance into the environment of use, the matrix comprising apharmaceutically acceptable non-toxic hydroxypropylcellulose thatabsorbs fluid from the gastrointestinal tract, expands and exhibits a 2to 50 fold volume increase and comprises a hydroxypropyl content of 7 to16%; and, (b) a plurality of tiny pills dispersed in the matrix, thetiny pills comprising:(1) a dosage amount of a beneficial drug; and, (2)a wall that surrounds the beneficial drug, the wall comprising in atleast a part of cellulosic polymer comprising an acetyl content of from21 to 44.8%.
 6. The drug delivery device for the controlled delivery ofa beneficial drug according to claim 5, wherein the reservoir releasesthe tiny pills over time and tiny pills release the beneficial drug overtime.
 7. The drug delivery device for the controlled delivery of abeneficial drug according to claim 5, wherein the environment of use isthe gastrointestinal tract, the tiny pills comprise from 10 mg to 50 mgof the beneficial drug, the beneficial drug is a gastrointestinaladministrable drug, and the delivery device exhibits gastric retention.8. A drug delivery device for the controlled delivery of a beneficialgastrointestinal administrable drug to the fluid environment of thegastrointestinal tract over a prolonged period of time, the deliverydevice comprising:(a) a matrix adapted for oral admittance into thegastrointestinal tract, the matrix comprising a pharmaceuticallyacceptable nontoxic hydroxypropylcellulose that absorbs fluid from thegastrointestinal tract, retains some fluid within its matrix structure,expands from 2 to 50 fold volume increase and comprises a hydroxypropylcontent of 7 to 16%; and, (b) a plurality of tiny pills dispersedthroughout the matrix, the tiny pills comprising:(1) a dosage amount ofa beneficial drug; and, (2) a wall that surrounds the beneficial drug,the wall comprising at least in part ethyl cellulose that releases thebeneficial drug when the delivery device is in use in thegastrointestinal tract over time.